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000306696 0247_ $$2ISSN$$a1091-6490
000306696 037__ $$aDKFZ-2025-02686
000306696 041__ $$aEnglish
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000306696 1001_ $$aLugassy, Jennie$$b0
000306696 245__ $$aDevelopment of DPP-4-resistant CXCL9-Fc and CXCL10-Fc chemokines for effective cancer immunotherapy.
000306696 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2025
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000306696 520__ $$aCXCR3 is a chemokine receptor for three ligands: CXCL9, CXCL10, and CXCL11. Accumulating evidence, including data presented here, suggests that the interaction between CXCL9/CXCL10 and CXCR3 not only attracts CXCR3+ T cells but also promotes the induction of IFNγ-high effector/cytotoxic CD4+ and CD8+ T cells, establishing a CXCL9/10-CXCR3-IFNγ self-amplifying cycle that promotes efficient cancer cell killing. One of the homeostatic mechanisms that may limit this cycle is the cleavage of the two N-terminal amino acids of these chemokines by Dipeptidyl Peptidase IV (DPP-4). The modified chemokines retain their ability to bind CXCR3 but no longer activate it, becoming competitive antagonists to native CXCL9/CXCL10. To develop a DPP-4-resistant variant, we combined biochemical analysis with computational modeling, demonstrating that the addition of N-terminal glutamine (Q) to CXCL9-Fc and CXCL10-Fc rendered them fully active CXCR3 agonists, yet resistant to DPP-4 cleavage. Preclinical evaluations imply that they offer significant therapeutic potential in cancer immunotherapy.
000306696 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000306696 650_7 $$2Other$$aCXCL10
000306696 650_7 $$2Other$$aCXCR3
000306696 650_7 $$2Other$$aDPP-4
000306696 650_7 $$2Other$$aT cell subsets
000306696 650_7 $$2Other$$aimmunotherapy
000306696 650_7 $$2NLM Chemicals$$aChemokine CXCL9
000306696 650_7 $$2NLM Chemicals$$aChemokine CXCL10
000306696 650_7 $$0EC 3.4.14.5$$2NLM Chemicals$$aDipeptidyl Peptidase 4
000306696 650_7 $$2NLM Chemicals$$aReceptors, CXCR3
000306696 650_7 $$2NLM Chemicals$$aCXCR3 protein, human
000306696 650_7 $$2NLM Chemicals$$aCXCL9 protein, human
000306696 650_7 $$2NLM Chemicals$$aCXCL10 protein, human
000306696 650_7 $$2NLM Chemicals$$aImmunoglobulin Fc Fragments
000306696 650_7 $$0EC 3.4.14.5$$2NLM Chemicals$$aDPP4 protein, human
000306696 650_2 $$2MeSH$$aChemokine CXCL9: genetics
000306696 650_2 $$2MeSH$$aChemokine CXCL9: metabolism
000306696 650_2 $$2MeSH$$aChemokine CXCL9: immunology
000306696 650_2 $$2MeSH$$aChemokine CXCL9: chemistry
000306696 650_2 $$2MeSH$$aChemokine CXCL10: genetics
000306696 650_2 $$2MeSH$$aChemokine CXCL10: metabolism
000306696 650_2 $$2MeSH$$aChemokine CXCL10: immunology
000306696 650_2 $$2MeSH$$aChemokine CXCL10: chemistry
000306696 650_2 $$2MeSH$$aDipeptidyl Peptidase 4: metabolism
000306696 650_2 $$2MeSH$$aDipeptidyl Peptidase 4: genetics
000306696 650_2 $$2MeSH$$aReceptors, CXCR3: metabolism
000306696 650_2 $$2MeSH$$aReceptors, CXCR3: immunology
000306696 650_2 $$2MeSH$$aHumans
000306696 650_2 $$2MeSH$$aImmunotherapy: methods
000306696 650_2 $$2MeSH$$aNeoplasms: therapy
000306696 650_2 $$2MeSH$$aNeoplasms: immunology
000306696 650_2 $$2MeSH$$aAnimals
000306696 650_2 $$2MeSH$$aMice
000306696 650_2 $$2MeSH$$aImmunoglobulin Fc Fragments: genetics
000306696 650_2 $$2MeSH$$aImmunoglobulin Fc Fragments: immunology
000306696 650_2 $$2MeSH$$aCell Line, Tumor
000306696 650_2 $$2MeSH$$aCD8-Positive T-Lymphocytes: immunology
000306696 7001_ $$aAbdala-Saleh, Noor$$b1
000306696 7001_ $$aJarrous, Ghada$$b2
000306696 7001_ $$aTurky, Abeer$$b3
000306696 7001_ $$00009-0008-6684-7876$$aSaidemberg, Daniel$$b4
000306696 7001_ $$00009-0009-8666-1320$$aRidner-Bahar, Gabriela$$b5
000306696 7001_ $$00000-0002-7008-9667$$aBerger, Nir$$b6
000306696 7001_ $$aBar-On, Dana$$b7
000306696 7001_ $$aTaura, Tetsuya$$b8
000306696 7001_ $$aWilson, David$$b9
000306696 7001_ $$00000-0003-2355-6661$$aKarin, Nathan$$b10
000306696 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.2501791122$$gVol. 122, no. 16, p. e2501791122$$n16$$pe2501791122$$tProceedings of the National Academy of Sciences of the United States of America$$v122$$x0027-8424$$y2025
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